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The microstructure, mechanical properties, and damping performance of Mg–4Li–3Al–0.3Mn alloy were systematically investigated in this research. The results show that the microstructure of Mg–4Li–3Al–0.3Mn alloy is significantly refined after extrusion. The average grain size of the as-extruded Mg–4Li–3Al–0.3Mn alloy is ∼1.5 μm and many nano-sized AlMn phases are precipitated during hot extrusion. The yield strength (YS), ultimate tensile strength (UTS), and elongation (EL) of the as-extruded Mg–4Li–3Al–0.3Mn alloys reach 248 MPa, 332 MPa, and 14.3%, respectively, which are higher than most of the reported Mg–Li alloys. The high strength of as-extruded Mg–4Li–3Al–0.3Mn alloy is associated with the refined grains, residual dislocations, and nano-sized precipitates. The as-extruded Mg–4Li–3Al–0.3Mn alloy has better damping properties than its as-cast counterpart, with the damping capacity (Q−1) of 0.028 and 0.022 at the strain amplitude of 1 × 10−3, respectively. The relatively high Schmid factor of non-basal slip and the high dislocation density are attributed to the improved damping performance.

The effect of Ca addition on the microstructure, mechanical properties, and corrosion behaviors of the extruded Mg−7Li−3Al alloys was investigated. The results showed that the extruded Mg−7Li−3Al−xCa alloys consisted of α-Mg (hcp) + β-Li (bcc) matrix phases and Al2Ca. With increasing Ca content, the amount and morphology of the Al2Ca phase changed significantly. The grains of the extruded Mg−7Li−3Al−xCa alloys were refined by dynamic recrystallization during the extrusion process. The tensile tests results indicated that the extruded Mg−7Li−3Al−0.4Ca alloy exhibited favorable comprehensive mechanical properties; its ultimate tensile strength was 286 MPa, the yield strength was 249 MPa, and the elongation was 18.7%. The corrosion results showed that this alloy with 0.4 wt.% Ca addition exhibited superior corrosion resistance, with a corrosion potential Ecorr of −1.48742 VVSE, attributed to the formation of protective Al2Ca phases.

The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.

The article provides insights into the study of noroviruses (NoVs), a leading cause of nonbacterial gastroenteritis. It discusses recent advances in understanding the tropism of NoVs for intestinal epithelial cells (IECs) and their sensitivity to antiviral cytokines, particularly interferons (IFNs). Additionally, it explores the role of tuft cells in the innate immune response to NoV infections.

Interferon-γ (IFN-γ) has been shown to enhance anti-tumor immunity and inhibit the formation of bone-resorbing osteoclasts. We evaluated the role of IFN-γ in bone metastases, tumor-associated bone destruction, and hypercalcemia in human T cell lympho-trophic virus type 1-Tax transgenic mice. Compared with Tax+IFN-γ+/+ mice, Tax+IFN-γ-/- mice developed increased osteolytic bone lesions and soft tissue tumors, as well as increased osteoclast formation and activity. In vivo administration of IFN-γ to tumor-bearing Tax+IFN-γ-/- mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN-γ directly decreased the viability of Tax+ tumor cells through inhibition of proliferation, suppression of ERK phosphorylation, and induction of apoptosis and caspase 3 cleavage. IFN-γ also inhibited macrophage colony- stimulating factor-mediated proliferation and survival of osteoclast progenitors in vitro. Administration of IFN-γ to C57BL/6 mice decreased Tax+ tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-γ treatment failed to protect IFN-γRF-/- mice from Tax+ tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-γ suppressed tumor-induced bone loss and hypercalcemia in Tax+ mice by inhibiting both Tax+ tumor cell growth and host-induced osteolysis. These data suggest a protective role for IFN-γ in patients with bone metastases and hypercalcemia of malignancy. [ABSTRACT FROM AUTHOR]

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss. [ABSTRACT FROM AUTHOR]

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptchl+/-) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch+/- mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. [ABSTRACT FROM AUTHOR]